There is recent evidence to suggest that TRH may be a potential antidepressant in humans following either intrathecal or systemic administration. The mechanisms underlying its antidepressant actions are unknown, although they appear to be independent of actions on thyroid function. Elucidating the mechanisms of action of may provide new insights for the development of novel pharmacotherapeutic agents in the treatment of depression. We have found that TRH did not affect the release of dopamine or levels of DA metabolites in the n. accumbens as assessed with microdialysis. Depletion of n.accumbens DA with 6-OHDA did not affect TRH-induced increases in general motor activity while reducing the incidence of wet dog shakes and paw licking. Depletion of forebrain serotonin did not significantly affect the increases in horizontal activity induced by TRH, while depletion of spinal serotonin decreased the number of wet dog shakes and paw licking. Increases in horizontal and vertical activity induced by TRH were not affected by vagotomy.